Researchers at the National Institute of Child Health and Human
Development have determined the sequence in which the malaria parasite
disperses from the red blood cells it infects. The National Institute
of Child Health and Human Development is one of the National Institutes
of Health.

The study appears in the September 20 Current Biology.

“It’s extremely important to learn about all aspects of the malaria
parasite’s life cycle, ” said Duane Alexander, M.D., Director of
the NICHD. “The parasite is growing resistant to the drugs used
to treat it, and new information is essential for developing strategies
to protect against the disease.”

The study supplants earlier theories on how the malaria parasite
spreads from the red blood cells it infects.

Malaria is caused by four species of the parasite Plasmodium,
the most common and deadly of which is Plasmodium falciparum.
P. falciparum spends part of its life cycle in the salivary glands
of mosquitoes and is transmitted to human beings through the bite
of infected mosquitoes. The parasite infects red blood cells. Called
a merozoite at the stage of its life when it infects red blood
cells, the parasite multiplies inside the cell, until the cell
ruptures and releases them. The newly released merozoites infect
still other cells, and the process begins again.

To conduct the study, the researchers stained red blood cells
infected with P. falciparum with two kinds of dye, explained the
study’s senior author, Joshua Zimmerberg, M.D., Ph.D., Chief of
NICHD’s Laboratory of Cellular and Molecular Biophysics. One dye
stained the blood cells green, the other stained the parasites
red.

In the first stage of the merozoites’ release, which the researchers
dubbed the “irregular schizont” stage, the red blood cell resembles
a lop-sided fried egg, with the parasites visible as a sphere near
the center of the cell. (A diagram of the entire sequence appears
at http://www.nichd.nih.gov/new/releases/malaria_graphic.cfm.) The cell’s lop-sided appearance probably
results from destruction of the cytoskeleton, the molecular scaffolding
that helps the cell to maintain its rounded shape.

In the next stage, called the “flower” stage, the red blood cell
assumes a roughly spherical shape, covered with rounded structures
that resemble the petals of a flower. Shortly thereafter, the blood
cell’s membrane appears to break apart. At roughly the same time,
cellular compartments, called vacuoles, which encase the newly
formed merozoites, also break apart. The entire process has an
explosive appearance, dispersing the merozoites some distance from
the cell.

During the release, Dr. Zimmerberg explained, the cell membrane
appears to collapse inward upon itself and fragment into pieces.

One previous theory held that the red blood cells and the merozoite-containing
vacuoles inside them swelled and then burst like a balloon containing
too much air.

“The swelling was an artifact of too much light from the microscope,” Dr.
Zimmerberg said. “The cell membrane was light sensitive. When we
turned the light down, we didn’t see the swelling.” Rather, he
said, upon release of the merozoites, the cell membrane appeared
to contract in upon itself.

Another theory held that the merozoite-containing vacuoles would
fuse with the cell membrane, and then release their contents.

“But we didn’t see any fusion,” Dr. Zimmerberg said.

The third theory held that the cell membrane ruptured, expelling
merozoite-containing vacuoles. Again, however, the researchers
observed that this theory also offered an inaccurate picture, as
the vacuoles ruptured at roughly the same time as the cell membrane.

Each step in the release process is a potential avenue for new
therapies to treat the disease, Dr. Zimmerberg said. By first understanding
how the parasite brings about each of these steps, it may be possible
to find ways to prevent each step from occurring.

The NICHD is part of the National Institutes of Health (NIH),
the biomedical research arm of the federal government. NIH is an
agency of the U.S. Department of Health and Human Services. The
NICHD sponsors research on development, before and after birth;
maternal, child, and family health; reproductive biology and population
issues; and medical rehabilitation.

The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U. S. Department of Health
and Human Services. It is the primary Federal agency for conducting
and supporting basic, clinical, and translational medical research,
and investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs,
visit http://www.nih.gov.